Process for preparing vanillylamine hydrochloride

ABSTRACT

Process for preparing vanillylamine or one of the salts thereof by reacting vanillin with hydroxylamine or the salts thereof in the presence of an organic salt, which may optionally be produced in situ, wherein the reaction is carried out in an inorganic or organic acid as diluent, and subsequently hydrogenating the resulting vanillyloxime with hydrogen in the presence of a suitable catalyst and an organic and/or inorganic acid.

RELATED APPLICATIONS

[0001] This application claims priority benefit of U.S. patentapplication Ser. No. 10/259,120, filed Sep. 27, 2002 and U.S.Provisional Application Serial No. 60/334,696, filed Nov. 20, 2001, bothof which are incorporated by reference herein in their entireties.

BACKGROUND TO THE INVENTION

[0002] The invention relates to a process for preparing vanillylaminehydrochloride which can be used on an industrial scale.

[0003] Vanillylamine hydrochloride is an intermediate product in thepreparation of pelargonic acid vanillylamide, which is used as ahyperemia inducing active substance, e.g. in plasters.

[0004] German Patent DE 760 746 describes the preparation ofvanillylamine hydrochloride, in which the isolated4-hydroxy-3-methoxy-benzaldoxime used as starting material is reducedusing hydrogen in the presence of activated charcoal and palladium oxidein an acetic acid solution and with the subsequent addition ofhydrochloric acid to obtain the vanillylamine hydrochloride.

[0005] The preparation of 4-hydroxy-3-methoxy-benzaldoxime from vanillinand hydroxylamine hydrochloride in a basic medium is described in theliterature (Ganett, P. M., J. Org. Chem. Vol. 53, No. 5, 1988). First,the oxime is isolated and then reduced to the amine in an ethanolichydrochloric acid solution. The isolation of the oxime represents asignificant expenditure of cost and time, particularly in the productionof vanillylamine hydrochloride on an industrial scale.

[0006] The problem overcome by the present invention is therefore toprepare a cost effective process for preparing vanillylaminehydrochloride which can be used on an industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention solves the problem described above by thefollowing method of synthesis.

[0008] The invention thus relates to a process for preparingvanillylamine or one of the salts thereof by:

[0009] a) reacting vanillin with hydroxylamine or the salts thereof inthe presence of an organic salt, which may optionally be produced insitu; and

[0010] b) subsequently hydrogenating the resulting vanillyloxime withhydrogen in the presence of a suitable catalyst and an organic and/orinorganic acid, wherein step a) is carried out in an inorganic ororganic acid as diluent.

[0011] In a preferred process, steps a) and b) are carried out in aone-pot process.

[0012] Also preferred is a process wherein step a) is carried out in thepresence of sodium acetate and glacial acetic acid.

[0013] In a particularly preferred process vanillin is reacted withhydroxylamine hydrochloride in step a).

[0014] Also particularly preferred is a process wherein Pd/C or Pt/C isused as catalyst in step b).

[0015] Of particular importance according to the invention is a processwherein the hydrogenation step b) is carried out in the presence ofglacial acetic acid and concentrated hydrochloric acid.

[0016] The invention preferably relates to a process wherein thereaction temperature in step a) is 15° C. to 50° C.

[0017] The invention preferably relates to a process wherein thereaction temperature in step b) is 0° C. to 70 C.

[0018] Particularly preferred is a process wherein vanillin is used in amolar ratio to hydroxylamine or the salt thereof of 1:2 to 2:1,preferably 1:1.

[0019] The invention also relates to the use of the vanillylamine or oneof the salts thereof obtained by the process according to the inventionfor preparing pharmaceutically active compounds.

[0020] The invention further relates to the use of the vanillylamine orone of the salts thereof obtained by the process according to theinvention for preparing pelargonic acid vanillylamide.

[0021] Acids suitable for forming salts of vanillylamine orvanillyloxime include, for example, hydrochloric acid, acetic acid,hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, succinicacid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaricacid, citric acid, ascorbic acid and methanesulphonic acid, particularlyhydrochloric acid, sulphuric acid or acetic acid.

[0022] In a preferred embodiment of the process according to theinvention for preparing the vanillylamine, as a rule one equivalent ofvanillin is suspended in 3 to 20 parts (based on the weight of vanillinused), preferably about 5 parts, of an acid diluent, preferably glacialacetic acid, hydrochloric acid or sulphuric acid, most preferablyglacial acetic acid, and combined with 1 to 2 equivalents, preferablyone equivalent of an organic salt, for example sodium hydroxide orsodium acetate, preferably sodium acetate, most preferably anhydroussodium acetate.

[0023] The suspension is combined with 1 to 2 equivalents, preferablyone equivalent, of hydroxylamine or a hydroxylamine salt, preferablyhydroxylamine hydrochloride or hydroxylamine sulphate, preferablyhydroxylamine hydrochloride, with stirring. The reaction mixture isheated to 25° C. to 50° C., preferably 28° C. to 40° C., more preferablyabout 30° C. to 35° C., and stirred for 0.5 to 8 hours, preferably about3 hours.

[0024] The vanillyloxime produced remains in suspension and ishydrogenated by the addition of 0.1 to 10 parts (based on the weight ofvanillin used), preferably about 0.7 parts, of acid, preferablyhydrochloric acid or sulphuric acid, more preferably hydrochloric acid,and 1 to 20% by weight (based on the vanillin used), preferably 10% byweight, of a catalyst, preferably a transition metal catalyst,preferably a Pd/C, Pt or Ra—Ni catalyst, most preferably a Pd/Ccatalyst, while hydrogen is piped into the reaction mixture, under ahydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, mostpreferably 4 bar, at a temperature of 0° C. to 70° C., preferably 10° C.to 35° C., preferably about 10° C.

[0025] Then the vanillylamine produced or the salt thereof is completelydissolved by the addition of water and optionally heating to 40° C. to70° C., preferably about 60° C.

[0026] The catalyst is filtered off. The filtrate is heated to 50° C. to70° C., preferably about 60° C., optionally after the diluent used,preferably acetic acid, has been distilled off, in order to dissolve thesalts and the vanillylamine or the salt thereof, and water is addedthereto. In order to precipitate the vanillylamine salt the reactionmixture is combined with an inorganic or organic acid, preferablyhydrochloric acid. The suspension formed is cooled and the salt of thevanillylamine is filtered, optionally washed with a solvent, preferablyacetone, and dried.

[0027] The procedure according to the invention results in a costeffective process with a high space/time yield with regard to thevanillylamine or the salts thereof.

[0028] The Examples that follow serve to illustrate some processes forpreparing vanillylamine or the salts thereof which are carried out byway of example. They should be understood as being only possibleprocedures described purely by way of example without restricting theinvention to their content.

[0029] Indeed, various modifications of the invention, in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description and accompanying drawings.Such modifications are intended to fall within the scope of the appendedclaims.

[0030] Various patent applications and publications are cited herein,the disclosures of which are incorporated by reference in theirentireties.

EXAMPLE 1 a) Synthesis of Vanillyloxime

[0031] 56.58 g of vanillin are suspended in 283 ml of glacial aceticacid and combined with 32.02 g of anhydrous sodium acetate. Then, 28.29g of hydroxylamine hydrochloride are added, the reaction mixture isheated to 30° C. to 35° C. with stirring and stirred for 30 hours.

b) Synthesis of Vanillylamine

[0032] The reaction mixture obtained in a) is combined with 38 ml ofhydrochloric acid and 6.2 g of Pd/C. Hydrogen is piped into the reactionmixture, with stirring, at 10° C. over a period of 4 hours under apressure of 4 bar. After the addition of 71 ml of water the mixture isheated to 60° C. and stirred for 1 hour. The catalyst is filtered offand the acetic acid is eliminated from the filtrate by distillation at60° C. Then the reaction mixture is combined with 141 ml of water inorder to dissolve the vanillylamine hydrochloride and the salts andstirred at 60° C. for 0.5 hours. After the addition of 99 ml ofhydrochloric acid and stirring for 1 hour, the suspension formed iscooled to 3° C. and after 3 hours the vanillylamine hydrochloride isfiltered off, washed with acetone and dried at 50° C.

[0033] Yield: 57.66 g (82% of theory).

EXAMPLE 2 a) Synthesis of Vanillyloxime

[0034] 20.0 g of vanillin are suspended in 150 ml of glacial acetic acidand combined with 8.6 ml of NaOH (50%). Then 10.96 g of hydroxylaminehydrochloride are added. The reaction mixture is stirred for 2 hours at20° C.

b) Synthesis of Vanillylamine Hydrochloride

[0035] The reaction mixture obtained in a) is combined with 27 ml ofhydrochloric acid and 2 g of Pd/C. Hydrogen is piped into the reactionmixture, with stirring, at 0° C. over a period of 2.5 hours under apressure of 4 bar. After working up, 13.12 g (53% of theory) ofvanillylamine hydrochloride are obtained.

What is claimed is:
 1. A process for preparing vanillylamine or a saltthereof comprising: a. reacting vanillin with hydroxylamine or the saltthereof in the presence of an organic salt, which may optionally beproduced in situ; and b. hydrogenating the resulting vanillyloxime withhydrogen in the presence of a suitable catalyst and an organic acid orinorganic acid or a combination of an organic and inorganic acid;wherein step (a) is carried out in an inorganic or organic acid asdiluent.
 2. The process according to claim 1, wherein steps (a) and (b)are carried out in a one-pot process.
 3. The process according to claim1, wherein sodium acetate and glacial acetic acid are used in step (a).4. The process according to claim 1 wherein vanillin is reacted withhydroxylamine hydrochloride in step (a).
 5. The process according toclaim 1 wherein Pd/C or Pt/C is used as catalyst in step (b).
 6. Theprocess according to claim 1 wherein the hydrogenation in step (b) iscarried out in the presence of glacial acetic acid and concentratedhydrochloric acid.
 7. The process according to claim 1 wherein thereaction temperature in step (a) is 15° C. to 50° C.
 8. The processaccording to claim 1 wherein the reaction temperature in step (b) is 0°C. to 70° C.
 9. The process according to claim 1 wherein the vanillin isused in a molar ratio to hydroxylamine or a salt thereof of 1:2 to 2:1.10. A pharmaceutical composition comprising a vanillylamine or a saltthereof obtained by the process according to one of claims 1 to
 9. 11. Acomposition comprising pelargonic acid vanillylamide obtained by aprocess for preparing pelargonic acid vanillylamide wherein a startingmaterial of the process for preparing pelargonic acid vanillylamidecomprises vanillylamine or a salt thereof obtained by the process forpreparing vanillylamine or a salt thereof according to one of claims 1to 9.